1. Field
The disclosure relates to a method for predicting patient responsiveness to treatments for rheumatoid arthritis involving a tumor necrosis factor superfamily member or a cytokine, to a method of monitoring the effectiveness of such therapy, and to a method for screening compounds for use in the treatment of rheumatoid arthritis. The disclosure also relates to a method for monitoring the disease state in rheumatoid arthritis patients.
2. Description of the Related Art
Autoimmune disease is characterized by production of either antibodies that react with host cells or immune effector T cells that are autoreactive. Autoantibodies are frequently identified in certain types of autoimmune disease, such as anti-acetylcholine receptor antibodies in myasthenia gravis and anti-DNA antibodies in systemic lupus erythematosus. However, such autoantibodies are not seen in many types of autoimmune disease. Moreover, autoantibodies are often detected among healthy individuals, but such antibodies do not induce autoimmune disease. Thus, beside autoantibodies, additional yet-to-be identified mechanisms are evidently involved in the pathogenesis of autoimmune disease.
Once autoantibodies bind to the target host cells, the complement cascade is thought to be activated to form the C5-9 membrane attack complex on the target cell membranes, which leads to the death of host cells (see Esser, Toxicology 87, 229 (1994)). Byproduct chemotactic factors, such as C3a, C4a, or C5a recruit more leukocytes to the lesion (see Hugh, Crit. Rev. Immunol. 1, 321 (1981)). Recruited leukocytes or naturally present leukocytes at the lesion recognize antibody-bound cells (immune complexes) via Fc receptors (“FcR”). Once the FcR is cross-bridged by the immune complex, leukocytes release TNF-α (see Debets et al., J. Immunol. 141, 1197 (1988)), which binds to specific receptors present on the surface of host cells, and induces apoptosis or cell damage (see Micheau et al., Cell 114, 181 (2003)). Activated FcR also initiates the release of chemotactic cytokines to recruit different subsets of leukocytes to the lesion (see Chantry et al., Eur. J. Immunol. 19, 189 (1989)). This is an overall hypothesis of the molecular mechanism of FcR-related autoimmune disease.
Rheumatoid arthritis (“RA”) is an immune disease involving inflammation of the gastrointestinal tract. Although it is well characterized clinically, its pathogenesis is poorly understood. RA is characterized by persistent inflammatory synovitis, usually involving peripheral joints in a symmetric distribution. This may lead to cartilage destruction, bone erosion, and changes in joint integrity. The cause of RA remains unknown, but it is strongly suspected that CD4+ T-cells play a role in the disease because of the predominance of such cells in the synovium, the increase in soluble IL-2 receptors (produced by activated T-cells) in the blood and serum of RA patients, and the noted amelioration of the disease by removal of T-cells. RA is associated with a buildup of TNF-α (also known as TNFSF-2) in the joints. TNF-α normally serves to mobilize white blood cells to fight infections and other invaders, causing inflammation in the affected area. A healthy body can rid itself of excess TNF-α, but the body of a patient with rheumatoid arthritis cannot. As a result, more and more white blood cells travel to the affected area. The build up of TNF-α, particularly in the rheumatoid joint, causes inflammation, pain and tissue damage.
IgG Fc receptors (FcγR) are known to react with immune complexes (ICs) (the combination of an epitope with an antibody directed against that epitope) to elicit various inflammatory reactions. ICs are frequently identified at joint lesions in patients with RA, although specific antigens have not been not fully characterized. ICs are also known to activate complement cascades to establish inflammation, as well as antibody-dependent cell mediated cytotoxicity (ADCC) by binding to the FcγR of various leukocytes. Locally infiltrating leukocytes have been collected from synovial fluids and studied previously. However, because these collections contain both newcomer and exhausted cells, the results have been difficult to interpret. Since peripheral blood leukocytes play a major role in the pathogenesis of RA when they migrate to disease sites, numerous experiments have been conducted to simulate such functions in vitro. Typically, mononuclear leukocytes are isolated, suspended in culture media, and incubated in a CO2 incubator with various stimulants or effector cells. However, the conditions under which such assays are conducted do not approximate physiological conditions, due to a lack of communication among different cell populations, oxygen supply from erythrocytes, as well as complex interactions with plasma proteins and other components. Secondary reactions may occur during the lengthy incubation period. Moreover, due to labor-intensive techniques and substantial experiment-to-experiment variations, these in vitro tests have less application in diagnostic testing.
Treatment of RA focuses on pain relief, reduction of inflammation, protection of articular structures, maintenance of function, and control of systemic involvement. Options include: aspirin and other nonsteroidal anti-inflammatory drugs; antirheumatic drugs such as methotrexate, gold compounds, D-penicillamine, the antimalarials, and sulfasalazine; glucocorticoids; TNF-α neutralizing agents such as infliximab and etanercept; and immunosuppressive drugs such as azathioprine, leflunomide, cyclosporine, and cyclophosphamide. Because the choice of therapeutic options depends on an assessment of the disease state in RA patients, it would be desirable to develop new methods of evaluating the disease state and monitoring the progression of the disease.